hypoglycemia

Introduction

Also see Whipple's triad

Classification

• fasting
• reactive (postprandial)

Etiology

• hypoglycemic agents
  • common among diabetics at all levels of glycemic control (HgbA1c) ~11% of patients/year
  • serious hypoglycemia in type 2 diabetes most common at high & low HgbA1c
  • causes in diabetics taking hypoglycemic agent(s)
    • meal-related misadventures, missing a meal (46%)
    • using wrong insulin product (22%)
    • wrong insulin dose or confusing dosing units (12%)
    • intentionally taking an additional dose (6.0%)
  • surreptitious use of hypoglycemic agent
  • hypoglycemic agents least likely to cause hypoglycemia
    • metformin
    • SGLT2 inhibitors (flozins)
    • GLP-1 receptor agonists (incretin mimetics, glutides)
    • tirzepatide
    • thiazolidinediones (glitazones)
    • dipeptidyl peptidase-4 inhibitors (gliptins)
• reactive (postprandial):
  • within 1st 5 hours after eating
  • infrequent, over diagnosed (self diagnosed);
    • rarely true hypoglycemia (glucose < 50 mg/dL)
    • unlikely to occur after eating in a patient with type 2 diabetes
      • see Differential diagnosis: (below)
  • gastrointestinal surgery
    • vagotomy, pyloroplasty, gastrectomy, gastrojejunostomy
  • early diabetes (unusual)
  • idiopathic "functional" hypoglycemia
• fasting:
  • more than 5 hours after eating
  • more common form of hypoglycemia
  • pharmacologic agents
    • insulin (including surreptitious injection)
    • oral hypoglycemics
    • quinine (intravenous for cerebral malaria)
    • alcohol impairs gluconeogenesis
    • propranolol (often in hemodialysis patients)
    • salicylates (mostly children)
    • pentamidine in undernourished AIDS patients
    • disopyramide (Norpace)
      • elderly non-diabetics with liver or renal failure
    • haloperidol
    • tramadol
  • renal insufficiency
  • severe malnutrition
  • pregnancy (generally asymptomatic)
  • hepatic failure: cirrhosis
  • septicemia
  • insulinoma:
    • may be benign or malignant
      • may occur as component of MEN-1
    • nesidioblastosis in children
  • hormone deficiency
    • adrenal insufficiency (more common in children)
    • growth hormone deficiency
    • thyroxine deficiency
    • catecholamine deficiency
    • glucagon deficiency (unusual)
  • abdominal tumors
    • mesenchymal tumor: abdomen, pelvis, thorax
    • carcinoma of the adrenal, kidney, GI tract
    • hepatoma
    • may be secondary to IGF-2
  • glycogen storage disease
  • systemic carnitine deficiency
  • congestive heart failure
  • leukemia may result in artifactual hypoglycemia
    • leukocyte consumption of glucose, use NaF tubes
  • insulin autoimmune hypoglycemia
    • anti-insulin & anti-insulin receptor antibodies
• relative hypoglycemia; plasma glucose > 70 mg/dL
• overnight hypoglycemia

Epidemiology

• hospital admission for hypoglycemia now exceed those for hyperglycemia among older adults

Clinical manifestations

• plasma glucose levels < 50 mg/dL usually, but not always produce hypoglycemia
  • fasting young, healthy women may have serum glucose levels < 50 mg/dL without symptoms
  • poorly controlled diabetics may experience symptoms of hypoglycemia > 70 mg/dL
• cholinergic symptoms
  • sweating
• adrenergic symptoms
  • anxiety
  • hunger, nausea
  • diaphoresis
  • tachycardia
  • tremulousness
  • PVC's
  • irritability
  • hyperthermia
  • palpitations
  • hypothermia
• neurologic symptoms
  • headache
  • behavioral changes (combativeness, agitation)
  • cognitive change
  • seizures
  • coma
  • hemiparesis
  • aphasia
  • visual changes
  • Babinski's sign
• nocturnal hypoglycemia may not cause awakening from sleep but lead to fatigue, sweating & headache in the morning

* syncope is NOT a manifestation

Diagnostic criteria

• see Whipple's triad

Laboratory

• serum glucose
  • hypoglycemia is defined as laboratory serum glucose or plasma glucose
    • < 54 mg/dL (serious hypoglycemia)
    • < 70 mg/dL
  • fasting serum glucose of < 50-60 mg/dL may occur in asymptomatic normal people & does not need further evaluation
• known diabetic
  • serum alcohol
  • serum cortisol level
  • liver function tests
  • serum urea nitrogen
  • serum creatinine
  • C-peptide in serum
    • elevated serum insulin with low C-peptide in serum suggests insulin overdose
  • sulfonylurea level if serum insulin & serum C-peptide are inappropriately increased for degree of hypoglycemia
• non-diabetic
  • 5 specimens 6 hours apart for fasting hypoglycemia ?? -> 30 hours
  • collect but do not analyze unless simultaneous serum glucose < 60 mg/dL
  • routine tests
    • serum insulin
      • serum insulin > 6 mU/mL in association with serum glucose < 50 mg/dL in males & < 40 mg/dL in females indicates hyperinsulinemia
    • serum proinsulin
    • C-peptide levels (obtain when glucose is < 50 mg/dL)
      • C-peptide level > 0.2-0.4 nM (0.9-4.0 ng/mL) suggests a beta-cell lesion (insulinoma) or serruptitious ingestion of sulfonylurea
      • plasma insulin with low plasma C-peptide suggests surreptitious injection of insulin
    • serum beta-hydroxybutyrate
  • mixed meal testing for postprandial hypoglycemia
    • baseline (routine tests except serum beta-hydroxybutyrate)
    • draw specimens 30 minutes apart for 5 hours
    • if serum glucose < 60 mg/dL, reanalyze baseline tests (see above)
  • insulin antibodies
  • anti-insulin receptor antibodies if insulin is increased, no insulin antibodies & C-peptide is normal or low
• 72 hour fast
  • increased serum insulin & serum C-peptide in the absence of insulin antibodies & measurable serum sufonylureas indicates insulinoma
• increased serum insulin-like growth factor-2 (serum IGF-2) suggests mesenchymal tumor
• 5 hour glucose tolerance test: (NOT useful)
  • serum glucose < 50 mg/dL with symptoms of hypoglycemia occurs commonly in normal individuals
• see ARUP consult

* do not use home glucometers to diagnose hypoglycemia

Diagnostic procedures

• continuous glucose monitoring in patients with diabetes mellitus

Radiology

• CT of abdomen
  • only after confirmation of elevated endogenous plasma insulin
  • not routinely indicated unless carcinoma (insulinoma) suspected

Complications

• even mild hypoglycemia associated with increased mortality in critically ill patients
• severe hypoglycemia is associated with increased risk of cardiovascular disease & death

Differential diagnosis

• self diagnosed hypoglycemia
  • anxiety
  • panic attacks
  • hyperventilation
  • pheochromocytoma
• neurologic manifestations of hypoglycemia
  • seizure disorder
  • psychosis
  • drug or alcohol intoxication
  • transient ischemic attack or stroke
  • etiologies of coma
• acute coronary syndrome in the elderly
  • nausea, vomiting, dyspnea after eating

Management

• asymptomatic hypoglycemia does not require treatment
• acute therapy
  • 6-12 oz (200-400 mL, 120-240 mL) of juice or non diet soda if awake
    • 15-25 g of glucose = 3-4 glucose tablets
  • 50 mL of 50% glucose IV: followed by 10% glucose IV until patient is able to eat
  • repeated boluses of 50% glucose may be required
  • fructose is alternative to glucose
  • glucagon 1 mg IV or IM if unresponsive
• treatment of underlying disorder
  • functional assessment/cognitive assessment for multiple episodes of hypoglycemia in elderly who had been stable on insulin-containing regimens for years
  • pseudo (self diagnosed) hypoglycemia
    • high protein diet, frequent meals
  • discontinue use of alcohol
  • discontinue or decrease sulfonylureas
    • substitute with metformin or shorter-acting sulfonylurea (i.e. glypizide)
  • adjust insulin dose
    • review functional status in elderly first
    • taper insulin in patients with type 2 diabetes (1st line)
    • switching from NPH to degludec, detemir or glargine my reduce episodes of hypoglycemia & improve glycemic control
      • degludec may be associated with less hypglycemia than glargine (RR=0.70)
    • continous glucose monitoring may be indicated
      • glycemic control variability & hemoglobin A1c not at goal
      • Medicare currently approves continuous glucose monitoring only for patients who require >= 3 insulin injections daily
  • discontinue other offending pharmacologic agents
  • patients with renal failure not on dialysis require higher carbohydrate diets with more frequent feedings
  • patients on dialysis may benefit from a decrease in dialysis glucose concentration
  • patients with hepatic failure require continuous intravenous glucose until recovery has begun
  • malnutrition requires adequate nutrients
  • cortisol replacement for adrenal insufficiency
  • insulinomas & mesenchymal tumors
    • consult endocrinology & surgery
    • non operable insulinomas may be managed with
      • diazoxide
      • thiazides
    • tumor debulking & chemotherapy for mesenchymal tumors
  • counseling may benefit anxiety disorder
  • psychiatric evaluation for factitious hypoglycemia
  • postprandial hypoglycemia due to gastrectomy or gastric bypass
    • small mixed meals containing protein, fat, high-fiber complex carbohydrates
• prevention
  • slow correction of long-standing hyperglycemia to avoid relative hypoglycemia by preventing large variations in blood glucose

Comparative biology

• glucose deprivation in a tauopathy mouse model triggers tau pathology & synaptic dysfunction
  • memory impairment
  • reduction of synaptic long-term potentiation
  • increased tau phosphorylation mediated by activation of P38 MAPK Kinase

More general terms

• sign/symptom

More specific terms

• familial hyperinsulinemic hypoglycemia; persistent hyperinsulinemic hypoglycemia of infancy (PHHI); congenital hyperinsulinism
• leucine-induced hypoglycemia; leucine-sensitive hypoglycemia of infancy
• neuroglycopenia
• overnight hypoglycemia; nocturnal hypoglycemia
• relative hypoglycemia

Additional terms

• glucose in serum/plasma
• hyperglycemia
• hypoglycemic agent

Component of

• Whipple's triad (Whipple's criteria)